Antibodies that cause allergic reactions also have potential as treatments for solid tumors, according to UCL researchers exploring the new field of allegro-oncology.
Immunoglobulin E (IgE) antibodies consist of two heavy chains and two light chains, with the ε chain containing four Ig-like constant domains. They are an important part of the immune response, particularly against parasites and infection by members of the helminth family of worms.
However, IgE antibodies are more commonly known for their role in life-threatening hypersensitivity reactions, including those associated with food allergies and related diseases like asthma and atopic dermatitis.
IgEs also have therapeutic potential according to Sophia Karagiannis, professor of Translational Cancer Immunology and Immunotherapy, King’s College London who spoke about the subject at the Antibody Engineering and Therapeutics conference in San Diego in December 2022.
“We know IgE deficiencies are associated with increased risk of cancer. So we think there are certain elements of IgE biology that might be of interest in cancer therapy.”
One such element is the binding affinity IgE antibodies have for FC receptors, which is 100,000 times higher than IgG antibodies have for their receptors. This higher affinity – which is part of the problem in allergic reaction – could help IgE based cancer drugs engage with their targets according to Karagiannis.
“[As a result of the higher affinity] there’s no need for immune complex formation for IgEs to be engaged and retained on the surface of cells. You only need a proportion of those IgEs engaged by a proportion of receptors for maximum activation of immune cells.”
Another useful feature is the fact IgE half-lives differ from other species, Karagiannis said.
“Persistence in tissues for IgE is about one or two weeks, whereas for IgG it is maybe two or three days. And the opposite is true in the blood where IgE is very quickly cleared from the blood. So maybe there is a chance in solid tumors that we can enhance availability.
“Interestingly, unlike IgG antibodies, IgE does not have an inhibitory FC receptor, so the button is only in the ‘on’ position after activation. So these are some features that we reasoned could be of interest in the context of cancer therapy.”
To test this, Karagiannis and colleagues made IgE class antibodies against cancer antigens – specifically folate receptor alpha which is overexpressed in some tumors – to see if they could trigger markers that were characteristic of a beneficial immune response.
And the initial results of work with xenograft models in rodents are promising. According to Karagiannis, who said: “We added IgE or the IgG antibody with immune cells in a human xenograph model that expressed the target. And although both IgG and IgE restricted tumor growth at the beginning, over time only IgE restricted growth.
“So we wanted to see if we can represent the patient setting more closely and we designed a patient derived model PDX from a patient with stage three grade three ovarian cancer.
“We then introduced again human immune cells with either IgE or IgG antibodies and we found that the animals that died fastest where those in the control group that received IgG. IgE doubled the survival time.”
The team also tested the approach in rat models – in a bid to represent the likely human immune response more accurately. Again, the results were promising.
“We could show that monocytes, microphages, eosinophils, mast cells and muscles and other immune cells expressed IgE receptors including the trimeric IgE receptor, which is found on monocytes and macrophages.”
And the effect was not limited to cancers expressing folate receptor alpha. The team developed an IgE antibody against a receptor that is over expressed in skin cancers and again found there was a marked impact on tumors.
“We found that only two doses of this antibody could restrict the growth of melanoma subcutaneous lesions compared to the equivalent IgG and the controls as well.”
“We also tested it in patient derives xenograft models…and IgE was able to prolong the survival of these mice and restrict the growth of metastasis.”
“In vitro, we were able to test the ability of IgE to trigger patient immune cells from a melanoma a cohort and we could show very clear activity of ADCC of melanoma cells, suggesting there is a mechanism of effector functions triggered by IgE that we can actually study ex-vivo.”
In addition, the IgE antibodies triggered pro-inflammatory pathways rather than those associated with allergic reaction, which Karagiannis said further underlines their potential.
“It is interesting to study other classes of antibodies, not just the classic IgGs and we think IgE has some potential for cancer therapy…and one way we can potentially activate and reconfigure the tumor macro environment.”